Application of Pd-catalysed amines arylation for the synthesis of benzopolyazamacrocycles

Article abstract of DOI:10.1016/S0040-4039(02)02841-1

Amination of 1,2- or 1,3-dihalobenzenes by linear polyamines in the presence of Pd(dba)2/BINAP catalytic system can serve as a convenient one-pot procedure for the synthesis of benzopolyazamacrocycles.

Full text of DOI:10.1016/S0040-4039(02)02841-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1433–1435
Application of Pd-catalysed amines arylation for the synthesis of
benzopolyazamacrocycles
Irina P. Beletskaya,a,* Alexei D. Averin,a,b Anatolii A. Borisenko,a Franck Denatb and
Roger Guilardb,*
aDepartment of Chemistry, Lomonosov Moscow State University, Leninskie Gory, Moscow, 119899, Russia
bLIMSAG (UMR 5633), Faculte´ des Sciences ‘Gabriel’, 6, Bd. Gabriel, 21100, Dijon, France
Received 9 December 2002; accepted 17 December 2002
Abstract—Amination of 1,2- or 1,3-dihalobenzenes by linear polyamines in the presence of Pd(dba)2/BINAP catalytic system can
serve as a convenient one-pot procedure for the synthesis of benzopolyazamacrocycles. © 2003 Elsevier Science Ltd. All rights reserved.
The elaboration of convenient approaches for the syn-
thesis of free and substituted polyazamacrocycles is an
important challenge due to their wide range of applica-
tions.1,2 To date a great number of synthetic methods
have been developed, but most of them utilize multi-
step and low-yielding procedures to form the aimed
macrocycles. For example, cyclam is prepared in 20%
yield according to a four-step template method.3 The
Richman and Atkins procedure, involving p-toluenesul-
fonyl protecting groups, allows the synthesis of cyclen
in high yield but is not ‘atom-economic’ and requires
large amounts of solvent and long reaction times.4
More recently, some authors have used the very conve-
nient bis-aminal route for the synthesis of polyaza-
macrocycles.5,6 It was of main interest to explore the
one-pot Pd-catalyzed synthesis of polyazamacrocycles
starting from dihalobenzenes and the desired linear
polyamines. Unlike benzocrown ethers, benzo ana-
logues of saturated polyazamacrocycles are poorly
investigated even though such systems may possess
versatile and useful complexing abilities.7,8 Buchwald’s
Pd(dba)2/BINAP catalytic system was chosen for our
purpose since we have previously used this method
successfully to synthesize macrocycles based on anthra-
cene and anthraquinone.9–12
First o-dibromobenzene 1 was reacted with tetraamine
2a. The reaction of equimolar amounts of 1 and 2a was
performed in boiling dioxane (c=0.01 M to avoid the
possible formation of oligomers), in the presence of 8
mol% Pd(dba)2, 9 mol% BINAP and 1.5 equiv. of
NaOtBu as a base. The desired benzocyclam 3 was
formed in a poor 12% yield together with a linear
compound 4 which is the product of tetraamine diaryla-
tion (16%). The strong donor effect of the amino group
in the intermediate resulting from the first amination
Scheme 1.
Keywords: macrocycles; Pd catalysis; amines; arylation.
* Corresponding authors. Tel./fax: 007 (095) 9393618 (I.P.B.); fax: 33 3 80 39 61 17 (R.G.); e-mail: beletska@org.chem.msu.su; rguilard@
u-bourgogne.fr
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02841-1

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I. Beletskaya et al. / Tetrahedron Letters 44 (2003) 1433–1435
should deactivate the substitution of the second
bromine atom. Consequently, the remaining primary
amino group of the polyamine chain in this intermedi-
ate readily reacts with a second molecule of o-dibro-
mobenzene, leading to the formation of 4 (Scheme 1).
bromine atom compared to chlorine in the amination
reaction may favour the diarylation reaction despite
quite high dilution conditions. The size of the cycle thus
formed is a major parameter in these competitive
reactions.
In order to promote the substitution at the ortho-posi-
tion, 2,6-dichlorobromobenzene 5 was reacted with var-
ious polyamines 2a–e (Scheme 2). The electron-
withdrawing character of the remaining chlorine atom
should compensate to some extent the deactivating
effect of the amino group formed upon bromine substi-
tution. Similar conditions (Pd(dba)2/BINAP 8/9 mol%,
1.5–2 equiv. NaOtBu, dioxane, c=0.01–0.02 M) were
used for all the experiments.
The reaction of m-dibromobenzene 8 with tetraamine
2c was also investigated. The reaction was performed
according to the same experimental conditions to pro-
duce the desired compound 9 in 39% yield (Scheme 3).
Attempts to prepare benzo analogues of diazacrown
ethers only resulted in the formation of linear products.
For instance, the reaction of 2,6-dichlorobromobenzene
5 with dioxadiamine 10 led to a mixture of monoaryl-
ated dioxadiamines 11 and 12 (Scheme 4). It has to be
noted that partial reduction of one chlorine atom is
observed. Such reduction reaction did not occur when
polyamines are used, which is in a good agreement with
our previous observations.13,14 Other catalytic systems
are now under investigation to promote the cyclization
when di- and trioxadiamines are used as precursors.
The corresponding benzotetraazamacrocycle 6 were
formed in variable yields. As expected, the use of
2,6-dichlorobromobenzene 5 instead of o-dibromoben-
zene 1 gave higher yields: the macrocycle 6a was
formed in 47% yield while benzocyclam 3 was obtained
in only 12% yield (Scheme 1). However, some reactions
led to undesirable open-chain compound 7 as a result
of the diarylation reaction of the polyamine. The yield
of the reaction giving the cyclic products 6 is obviously
dependent on polyamine chain length and rigidity.
These results suggest that the higher reactivity of the
To summarize, a simple one-pot procedure for the
synthesis of benzo analogues of polyazamacrocycles is
described. Macrocyclic polyamines of different size,
Scheme 2.
Scheme 3.

I. Beletskaya et al. / Tetrahedron Letters 44 (2003) 1433–1435
1435
Scheme 4.
incorporating 1,2- and 1,3-disubstituted benzene moi-
eties, have been synthesized. It is obvious that the
reaction yields are strongly dependent on the length of
the polyamine chain.
(2C), 49.5 (2C), 121.3 (2C), 125.3 (4C), 128.8 (4C),
143.0 (2C).
2,5,9,12 - Tetraazabicyclo[11.3.1]heptadeca - 1(16),13(17),
14-triene 9: 1H NMR†: 1.60 q (2H, 5.3), 2.75 t (4H, 6.0),
2.80 t (4H, 5.7), 3.39 t (4H, 5.9), 5.98 dd (2H, 7.9, 2.2),
6.37 t (1H, 2.1), 6.91 t (1H, 7.9). 13C NMR: 25.7 (1C),
42.9 (2C), 48.4 (2C), 48.7 (2C), 95.0 (1C), 103.4 (2C),
128.9 (1C), 148.4 (2C). MALDI-TOF [M+] 234.66 (calc.
234.18).
Typical experimental procedure
In a two-neck flask flushed with argon, were added aryl
halide 1, 5 or 8 (1 mmol), polyamine 2 or 10 (1 mmol),
Pd(dba)2 (46 mg, 0.08 mmol), BINAP (55 mg, 0.088
mmol) and NaOtBu (300–400 mg, 1.5–2 mmol) in dry
dioxane (50–100 ml). The reaction mixture was refluxed
for 50–70 h under argon, then dioxane was evaporated
under reduced pressure and the residue was taken up
with CH2Cl2 (30 ml) and washed with water (15 ml).
The aqueous layer was extracted with CH2Cl2 (20 ml),
and the combined organic layers were dried over anhy-
drous Na2SO4. The solvent was evaporated under
reduced pressure, and the crude product was chro-
matographed on silica using successively CH2Cl2 and
CH2Cl2/CH3OH/NH3 30:6:1 (CH2Cl2/CH3OH 3:1 in
the case of 11, 12).
References
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Selected spectroscopic data
7. Lindoy, L. F. The Chemistry of Macrocyclic Ligand Com-
plexes; Cambridge University Press: Cambridge, 1989.
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1 - Chloro - 5,6,7,8,9,10,11,12,13,14,15,16 - dodecahydro-
5,9,12,16-tetraazabenzocyclotetradecene 6a: 1H NMR
(300 MHz, CDCl3): lH, ppm (J, Hz)†: 1.84 q (4H, 4.7),
2.79 m (4H), 2.86 t (2H, 5.3), 2.91 t (2H, 5.2), 2.96 t
(2H, 5.5), 3.22 t (2H, 5.3), 6.46 dd (1H, 8.1, 1.3), 6.67
dd (1H, 8.1, 1.3), 6.90 t (1H, 8.1). 13C NMR (75 MHz,
CDCl3): lC 26.3, 28.5, 45.1, 45.9, 46.4, 47.1, 48.0, 49.6,
107.7, 115.6, 124.5, 128.5, 130.7, 144.8. MALDI-TOF:
[M+] 282.84 (calc. 282.16).
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metry 2000, 11, 1703–1707.
11. Beletskaya, I. P.; Averin, A. D.; Bessmertnykh, A. G.;
Guilard, R. Tetrahedron Lett. 2001, 42, 4983–4986.
12. Beletskaya, I. P.; Averin, A. D.; Bessmertnykh, A. G.;
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N-(2,6-Dichlorophenyl)-N%-(2-{2-[2-(2,6-dichlorophenyl-
amino) - ethylamino] - ethylamino} - ethyl) - ethane - 1,2 - di-
1
amine 7d: H NMR: 1.83 br s (3H), 2.73 br s (8H), 2.82
t (4H, 5.7), 3.40 m (4H), 4.55 br s (2H), 6.73 t (2H, 8.1),
14. Guilard, R.; Bessmertnykh, A. G.; Beletskaya, I. P. Tet-
7.19 d (4H, 8.1). 13C NMR: 46.9 (2C), 49.0 (2C), 49.4
rahedron Lett. 1999, 40, 6393–6397.
† NH protons are not indicated.